Inproceedings: An article in a conference proceedings.
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Dysregulation of Glutathione Metabolism: A Risk Factor for Schizophrenia
Schizophrenia is a complex multi-factorial psychiatric brain disorder. It affects individuals at the centre of their personality and concerns about 1% of the world population. Both environmental and genetic factors are implicated in the vulnerability to develthis disease. Previous studies showed reduced levels of glutathione (GSH), the main non protein cellular redox regulator, both in cerebrospinal fluid and prefrontal cortex of schizophrenia patients (Do et al. 2000). In case-control association studies for candidate genes of GSH metabolism we found a strong association between schizophrenia and single nucleotide polymorphisms in the GSH key synthesizing enzyme glutamate- cysteine-ligase (GCL) modifier subunit (GCLM) gene (Tosic et al. submitted). In this study we investigated if these genetic anomalies led to functional consequences at the protein expression, as well as at the enzyme activity levels. Since GSH is ubiquitously present in cells, these parameters of the GCL regulation were determined in fibroblasts derived from skin biopsies. Moreover, in the GCLM knock-out mouse model it was observed that the luck of GCLM led to an increased sensitivity to oxidative stress (Yang et al. 2002). We thus compared between patients and controls the functional parameters at baseline, as well as under oxidative stress induced conditions by treating cells with tert-buthylhydroquinone, a substance known to produce reactive oxygen species. In the presented study we observed that compared to controls schizophrenia patients had a reduced GCL activity under oxidative stress conditions, a reduced protein expression of GCLC under baseline, as well as under oxidative stress conditions, and an uncoupling of GCLM and GCLC protein expression in response to oxidative stress. Finally, in the group of patients we observed an inverse correlation between the levels of GSH increase under oxidative stress conditions and the severity of positive symptoms of the disease.
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